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At a glance

Genetic disorder affecting the branched-chain organic acids, the most frequent of the leucine metabolism disorders. It is a classical type of organic academia. In 50% of cases, the onset of the disease becomes apparent within a few days after birth. This inborn error of metabolism leads to body accumulation of isovaleric acid (and its metabolites) resulting in vomiting, dehydration, severe metabolic acidosis, and neurologic manifestations. A characteristic feature of isovaleric acidemia is a very distinctive and strong odor of sweaty feet. This odor results from accumulation of the compound isovaleric acid.

Synonyms

Isovaleric Acid CoA Dehydrogenase Deficiency; Isovaleric Aciduria.

Incidence

Isovaleric acidemia is estimated to affect at least 1 in 250,000 births in the United States. A 2011 review of 176 cases found that early diagnosis immediately after birth was associated with a mortality of 33%. For the later onset of symptoms, mortality was only 3%.

Genetic inheritance

Autosomal recessive; chromosome 15q14-q15.

Pathophysiology

Isovaleryl-CoA dehydrogenase catalyzes the first step of branched-chain organic acid metabolism of leucine. The deficiency of isovaleryl-CoA dehydrogenase activity results in accumulation of abnormal metabolites (isovaleric acid, isovalerylglycine, hydroxyisovaleric acid, isovalerylglucuronide, isovalerylglutamic acid). The build-up of these metabolites is responsible for the disease. The precise mechanism of isovaleric acid toxicity is not well known, but it is an inhibitor of succinate CoA ligase in the Krebs cycle and inhibits liver mitochondrial oxygen consumption with glutamic, 2-oxoglutaric, and succinic acids. The neutropenia often seen in the disease may be attributed to inhibition of granulopoietic progenitor cell proliferation by isovaleric acid.

Diagnosis

Clinical course; occasionally foul odor of “sweaty feet” caused by isovaleric acid in body fluids; metabolic acidosis with mild-to-moderate ketonuria and lactic acidemia; hyperammonemia. Thrombocytopenia, neutropenia, and pancytopenia may be present, as well as hypocalcemia. The “sweaty feet” odor is suggestive of, but not specific for, isovaleric acidemia because it may be present in other organic acidurias (eg, “maple syrup” urine disease, glutaric aciduria Type II). Urine analysis for nonvolatile organic acids reveals marked elevation of isovalerylglycine acid with lesser elevation of hydroxyvaleric acid and smaller, but still significant, amounts of the other abnormal metabolites. Confirmation of the diagnosis of isovaleric acidemia comes from assays on patients’ fibroblasts showing deficiency of isovaleryl-CoA dehydrogenase (improved tritium release assay or fluorometric assay). Prenatal diagnosis can be made by amniocentesis by stable isotope dilution analysis of elevated isovalerylglycine in amniotic fluid or by fluorometric assay of isovaleryl-CoA dehydrogenase activity.

Clinical aspects

Two clinical categories: half of the patients present with an acute neonatal illness with poor feeding, dehydration, hypothermia, and coma, and if untreated, death secondary to severe metabolic acidosis, cerebral edema, cerebral hemorrhage, or infection. The other half of patients either are survivors of the acute neonatal ...

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